For several years, Joseph treated his priesthood more as a career than a vocation. Then one night he was called to the bed of a poor, sickwoman in labour. The woman badly needed medical help, but had been turned away everywhere for lack of money. Joseph stayed with her throughout the travail, and was there to hear her confession, give her absolution, Communion, and last rites. He baptized her newborn daughter, and then watched as both of them died in bed. The trauma of the evening changed his mind about his vocation.

In 1827 he opened a small shelter for the area sick and homeless, renting a room, filling it with beds, and seeking male and female volunteers. The place expanded, and he received help from the Brothers of Saint Vincent and the Vincentian Sisters. During a cholera outbreak in 1831, the local police closed the hospice, fearing it was a source of the illness.

In 1832, Giuseppe transferred his operation to the Valdocco area of Turin, Italy, and called the shelter the Little House of Divine Providence (Piccola Casa). The Casa began receiving support, and grew, adding asylums, orphanages, hospitals, schools, workshops, chapels, alm-shouse, and programs to help the poor, sick, and needy of all types. This small village of the poor depended almost entirely on alms, Joseph kept no records, and turned down offers of state assistance; never once did they do without. Joseph directed the operation until a few days before his death, and the Casa continues to today, serving 8,000 or more each day. He founded fourteen communities to serve the residents, including the Daughters of Compassion, Daughters of the Good Shepherd, Hermits of the Holy Rosary, and Priests of the Holy Trinity.

When I am in Heaven, where everything is possible, I will cling to the mantle of the Mother of God and I will not turn my eyes from you. But do not forget what this poor old man has said to you. – Saint Joseph from his deathbed